An immune response occurs only if a T lymphocyte has been able to recognize the foreign antigen in association with a self molecule encoded by the major histocompatibility complex (MHC). These self molecules expressed on antigen-presenting cells are the polymorphic class II MHC antigens. Most foreign antigens must be processed in order to bind to MHC molecules. Antigen processing for presentation by class II molecules generally involves endocytosis of antigen into an acidic compartment through which newly synthesized class II molecules travel on their way to the cell surface. Once at the cell surface the foreign peptide/MHC class II complex interacts with the T cell receptor and the CD4 molecule expressed on the antigen-specific T cell. The aim of this project is to define the function of human class II molecules in their interaction with T cells and the requirements for class II-restricted processing and presentation of viral antigens to CD4-positive T cells. It was demonstrated that several endogenous processing pathways lead to the presentation of cytosolic antigen to class II-restricted T cells. Most interestingly, one of the processing pathways was different from the one utilized for presentation by class I molecules. This unsuspected presentation of endogenous proteins by class II molecules has important implications on the T cell repertoire selection, on T cell tolerance, and on autoimmunity. Several staphylococcal toxins bind to class II molecules and have a strong mitogenic effect on T cells by stimulating entire families of T cells with particular Vbeta chains in their TCR. These toxins are representative of the newly described superantigens that do not require processing for presentation. the invariant (Ii) chain, bound to newly synthesized class II molecules, serves as a chaperon for the transport of class II molecules to an endocytic compartment where it dissociates from class II prior to the binding of immunogenic peptides and the cell surface appearance of peptide/class II complexes. It had been suggested that superantigens utilized the Ii chain binding site of class II molecules. However, it was shown that the binding site of HLA-DR for the 7 toxins tested was distinct from that for the HLA-DR-associated Ii chain. In addition, cell surface class II/Ii chain complexes were still able to stimulate T cells by superantigen. An important implication from this finding is that endogenous superantigens encoded by pathogens may bind to class II molecules intracellularly prior to the dissociation of the Ii chain.